Project 2: Current Good Manufacture Practices (CGMP) Production of Nucleoside-Modified mRNAs Encoding HIV-1 Envelopes This IPCAVD grant seeks to develop and evaluate mRNA as an HIV-1 vaccine platform. Project 2 will oversee the manufacture of two nucleoside-modified mRNAs by current good manufacturing practices (CGMP) for a Phase I clinical trial to begin in year 5. To execute this project, we will select contract development and manufacturing organizations (CDMOs) as commercial partners to manufacture two mRNA immunogens to induce V3-glycan envelope site-targeted bnAb precursors. The scope of this work will span knowledge transfer to the selected CDMO through successful IND filing for the final vaccine candidate. A technical CDMO management team, including Drs. Haynes, Weissman and Porter will be assembled to oversee the process and ensure successful delivery of the program. The following specific aims are proposed for the project. ? Aim 1. Facilitate knowledge transfer for selected mRNA immunogens to CDMOs. ? Aim 2. Deliver final drug substances and drug products for toxicology studies and clinical testing. ? Aim 3. Develop and deliver regulatory strategy to enable Phase I proof of concept clinical studies. Project 2 will advance modified mRNA as a platform for HIV immunization and establish the regulatory framework for its use. CGMP production of an mRNA V3-glycan mimetope vaccine will allow this vaccine platform to be evaluated in humans for comparison to other vaccination strategies and to assess the induction of V3-glycan bnAb precursors. Once developed, this platform could be rapidly applied to other HIV-1 immunogens with little additional development since the production process and the majority of release methods are not sequence dependent. These features of modified mRNA position the platform to address the complexity, safety, and cost effectiveness of HIV-1 vaccine regimens.